Efficacy and safety studies of gantenerumab in patients with Alzheimer’s disease

Panza, Francesco; Solfrizzi, Vincenzo; Imbimbo, Bruno P.; Giannini, Michele; Santamato, Andrea; Seripa, Davide; Logroscino, Giancarlo

doi:10.1586/14737175.2014.945522

Cited by 44 publications

(26 citation statements)

References 60 publications

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“…Passive immunization approaches using monoclonal antibodies against Aβ1-40 [103], Aβ1-42 [104], pyroglutamate Aβ [105], oligomers [106], or protofibrils [107][108][109] have been developed. Currently, clinical trials with the antibodies BAN2401 (recognizing protofibrils) [75], crenezumab (aggregated species) [76], gantenerumab (fibrils) [78][79][80], and solanezumab (Aβ mid-domain) [81,82] are ongoing (Table 1). However, other programs using antibodies such as bapinezumab (N-terminus) [110] and ponezumab (Cterminus) [111] have been discontinued as they did not meet expected goals.…”

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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“…Since these therapies have been offered to patients with moderate or early AD, it has been proposed that the neuronal damage is far too advanced in these symptomatic patients to observe significant benefits. These mostly disappointing results have led many leading scientists to doubt the only solid theory explaining AD pathogenesis, i.e., the amyloid hypothesis [45,62,63,64,65,66]. Ongoing trials on solanezumab and aducanumab in at-risk carriers of pathogenic AD mutations and individuals in the prodromal phase are expanding.…”

Section: Discussionmentioning

confidence: 99%

“…Results in preclinical models support the ability of gantenerumab to mediate Aβ42 clearance by microglia and reduce Aβ42 neurotoxicity without altering plasma Aβ42 levels [44]. Gantenerumab seems effective in reducing brain plaque in PET studies [45], but 2 patients experienced ARIA in a phase I trial. Several phase III trials are ongoing in carriers of familial AD mutations, patients in the prodromal phase, and patients with mild cognitive impairment (MCI) (Alzforum).…”

Section: Conformational Aβ42 Antibodiesmentioning

confidence: 99%

Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target

Wang¹,

Yan

Hong³

et al. 2017

Neurodegener Dis

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Background: Available drugs for the global Alzheimer disease (AD) epidemic only treat the symptoms without modifying disease progression. Accumulating evidence supports amyloid-β42 (Aβ42)as the key triggering agent in AD, making it the ideal target for disease-modifying therapies. Preclinical studies provided extensive support for passive Aβ42 immunotherapy, leading to human clinical trials with different antibodies. Objective: Examine the status of clinical trials for passive immunotherapy against Aβ42. Methods: We performed a thorough literature review of passive Aβ42 immunotherapy. Results: Ten anti-Aβ42 antibodies targeting lineal or conformational epitopes have been tested in clinical trials. Antibody engineering and appropriate dosing have overcome undesired side effects, leading to increased safety profiles. Unfortunately, few trials have shown cognitive protection, leading to legitimate questions about the utility of Aβ42 as an AD target. There is still hope that solanezumab, aducanumab, and other ongoing trials will identify antibodies, patient subpopulations, and administration protocols, with consistent clinical benefits. Conclusions: Despite the overall disappointing results, there is still hope that Aβ immunotherapy in presymptomatic patients will prevent neuronal loss and provide significant clinical benefits that can be applied to larger populations as preventive therapies. Advances with other targets may soon provide additional therapeutic options for AD with increased efficacy.

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“…All three compounds are highly selective for binding aggregated Aβ in the brains of human subjects (93–96). As with PiB, these 18 F-labeled Aβ imaging agents are used to detect the presence of Aβ deposits in brain for diagnostic purposes and in conjunction with drug therapy clinical trial studies (97–100). Appropriate use criteria for these agents have recently been established (101–105), and Procedure Standards and Practice Guidelines have been recommended by the Society of Nuclear Medicine and Molecular Imaging and the European Association of Nuclear Medicine (106).…”

Section: Selective Aβ Imaging Agentsmentioning

confidence: 99%

Small-molecule PET Tracers for Imaging Proteinopathies

Mathis

Lopresti

Ikonomović

et al. 2017

Seminars in Nuclear Medicine

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In this chapter, we provide a review of the challenges and advances in developing successful positron emission tomography (PET) imaging agents for three major types of aggregated amyloid proteins – amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn). These three amyloids are involved in the pathogenesis of a variety of neurodegenerative diseases, referred to as proteinopathies or proteopathies, that include Alzheimer’s disease, Lewy body dementias, multiple system atrophy, and frontal temporal dementias among others. In the Introduction, we briefly discuss the history of amyloid in neurodegenerative diseases and describe why progress in developing effective imaging agents has been hampered by the failure of crystallography to provide definitive ligand-protein interactions for rational radioligand design efforts. Instead, the field has relied on largely serendipitous, trial and error methods to achieve useful and specific PET amyloid imaging tracers for Aβ, tau, and α-syn deposits. Because many of the proteopathies involve more than one amyloid protein, it is important to develop selective PET tracers for the different amyloids to help assess the relative contribution of each to total amyloid burden. We utilize Pittsburgh Compound B (PiB) to illustrate some of the critical steps in developing a potent and selective Aβ PET imaging agent. Other selective Aβ and tau PET imaging compounds have followed similar pathways in their developmental processes. Success for selective α-syn PET imaging agents has not been realized yet, but work is ongoing in multiple laboratories throughout the world. In the tau sections, we provide background regarding 3-repeat (3R) and 4-repeat (4R) tau proteins and how they can affect the binding of tau radioligands in different tauopathies. We review the ongoing efforts to assess the properties of tau ligands, which are useful in 3R, 4R or combined 3R/4R tauopathies. Finally, we describe in the α-syn sections recent attempts to develop selective tracers to image α-synucleinopathies.

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Efficacy and safety studies of gantenerumab in patients with Alzheimer’s disease

Cited by 44 publications

References 60 publications

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target

Small-molecule PET Tracers for Imaging Proteinopathies

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